Thoracic Aortic Aneurysm and Dissection (TAAD) and Related Disorders. A Guide for

Transcription

1 Thoracic Aortic Aneurysm and Dissection (TAAD) and Related Disorders A Guide for

2 Thoracic Aortic Aneurysm and Dissection (TAAD) and Related Disorders Introduction Thoracic aortic aneurysm and dissection (familial TAAD) is a genetically heterogeneous disorder that can lead to aortic aneurysms, aortic dilatations, aortic dissections and aneurysms of the other arteries (i.e., abdominal, cerebral). Aneurysms often occur in the ascending aorta, resulting in progressive enlargement of the vessel diameter as measured by aortic imaging. Weakening and tearing of the luminal tissue layer of the aorta (the intima) can lead to aortic dissection, in which blood is forced through the tear into the wall of the vessel, separating the endothelial tissue layers from each Ascending Aorta Descending Thoracic Aorta Abdominal Aorta Thoracic Aortic Aneurysm Adapted from Cleveland Clinic Figure 1: Illustration showing a normal aorta (left) and a thoracic aortic aneurysm (right). other. Aortic dissection is a potentially life-threatening situation, and in rare instances can lead to rupture of the aorta and internal hemorrhage. Clinical Presentation/Course Patients with aortic aneurysm(s) are often asymptomatic. If the aneurysm progresses to dissection, patients will describe severe, sharp pain in the chest, back or abdomen, depending on the location of the dissection. Many patients with an aortic aneurysm will only be discovered upon routine testing, such as a chest Computed Tomography (CT) scan for an unrelated indication. The most serious complication of an aneurysm or dissection is rupture, which is often life threatening. Diagnosis Thoracic aneurysms, even when they are large, may not cause symptoms until they rupture. Therefore, it is important to identify individuals who are at high risk based on family history and genetic testing. Methodologies used for surveillance and diagnosis in individuals who are at risk or affected by TAAD include: Physical Examination Of particular importance in TAAD is the presence of clinical features 1

3 of connective tissue diseases as well as other findings that have been associated with TAAD (livedo reticularis, iris flocculi). The physical exam can help provide clues to differentiate TAAD from a connective tissue disease or another related genetic syndrome. Family History A family history of an aneurysm, early or sudden death and/or individuals with features of connective tissue diseases are important clues to identifying individuals at-risk for TAAD. Cardiac Evaluation Screening and surveillance may be performed using imaging studies such as: Computed Tomography (CT) Scan, Magnetic Resonance Imaging (MRI), Magnetic Resonance Angiography (MRA) and Echocardiogram. Genetic Testing Information obtained from the patient s age, physical exam, family history and imaging can help determine if genetic testing is appropriate. Etiology Genetic The genetic basis of TAAD has expanded rapidly over the past decade. While originally associated only with connective tissue diseases, there is increasing recognition that familial thoracic aneurysm and/or dissection can be an isolated finding in families. Up to 20% of patients with TAAD will have an affected first degree relative. 1 In most cases, TAAD is inherited in an autosomal dominant manner. Familial TAAD tends to occur at a younger age than a sporadic aneurysm, but the age of onset and presentation can vary among family members. Familial TAAD may occur as an isolated trait, or it may be a manifestation of a connective tissue disease or other genetic syndrome. Familial TAAD is diagnosed by the presence of dilatation and/or dissection of the thoracic aorta, the presence of a family history of TAAD and the absence of clinical features associated with connective tissue syndromes (i.e., Marfan syndrome, Ehlers-Danlos syndrome or Loeys-Dietz syndrome). 1 Individuals with isolated TAAD may have other findings, including aneurysms in the abdominal aorta, cerebral arteries or peripheral arteries, as well as patent ductus arteriosus (PDA), bicuspid aortic valve (BAV), livedo reticularis (purplish skin rash) or iris flocculi. Connective tissue plays an important role in many different organ systems. Therefore, individuals with a connective tissue disorder may present with symptoms in multiple organ systems, including skin, eyes, bones and joints. TAAD Clinician's Guide 2

4 Turner syndrome (45, X), Neurofibromatosis type 1 and autosomal dominant polycystic kidney disease (ADPKD) can also cause an aneurysm but should present with other findings early enough to separate from TAAD and other connective tissue diseases (Table 1). Risk Factors Other non-genetic risk factors for an aneurysm include increasing age, male sex, hypertension, tobacco use, coronary artery disease (more typical with abdominal aortic aneurysm) and isometric exercise. Blunt trauma to the chest can also cause an aneurysm in rare cases. Some infectious diseases (Syphilis and Tuberculosis) also can cause an aneurysm. TABLE 1 Genes Associated with TAAD and Connective Tissue Diseases GENE FBN1 TGFBR1 TGFBR2 MYH11 COL3A1 COL5A1 COL5A2 ACTA2 FBN2 SMAD3 CBS SLC2A10 TGFB2* FLNA* MED12* SKI* MFS: Marfan syndrome TAAD: Thoracic aortic aneurysm and dissection FEL: Familial ectopia lentis MASS: Mitral valve prolapse, aortic enlargement, skin and skeletal findings LDS: Loeys-Dietz syndrome ASSOCIATED DISEASE MFS, TAAD, FEL, MASS LDS, TAAD LDS, MFS, TAAD TAAD EDS III, IV EDS I, II EDS I TAAD CCA TAAD Homocystinuria ATS LDS, TAAD EDS III, PVNH LS SGS EDS: Ehlers-Danlos syndrome CCA: Congenital contractural arachnodactyly ATS: Arterial tortuosity syndrome PVNH: Periventricular nodular heterotopia LS: Lujans syndrome SGS: Shprintzen-Goldberg syndrome *These genes are only included on our TAAD sequencing panel Clinical Utility of TAAD Genetic Testing There are multiple ways genetic testing for TAAD and related disorders can benefit your patients. If positive, genetic testing in an individual with an aneurysm and/or connective tissue disease could: Confirm a clinical diagnosis in symptomatic patients Differentiate between familial TAAD, Marfan syndrome, Loeys-Dietz syndrome and other phenotypically related disorders Establish the genetic cause of an idiopathic aneurysm Provide information about prognosis Assists with selection of optimal surveillance and treatment options; in some cases this can be genotype-specific 3

5 Provides predictive testing for asymptomatic family members of a proband with a known disease-causing mutation associated with a genetic form of an aneurysm or a related disorder, which will: Enable clinical monitoring, follow-up, and optimal treatment when symptoms develop in an individual with a positive result Reduce anxiety and forego clinical monitoring if result is negative Provides genetic counseling, recurrence risk determination and family planning Genetic Test Results and What They Mean There are three possible outcomes of genetic testing: a positive result, a negative result or a variant of unknown significance (VUS). A positive result indicates that a disease-causing mutation was identified in the tested individual. This finding confirms the diagnosis. This information provides valuable information to the physician and family members about treatment, prognosis and recurrence risk. All firstdegree relatives (e.g., children, siblings and parents) of a patient with a positive genetic test result can then be offered predictive genetic testing. If a family member is found to be positive for the familial mutation, this individual is also at risk to develop an aneurysm or other symptoms of the connective tissue syndrome associated with the mutation, and should be referred for further evaluation. It is important to note that there is variability in symptoms, age of onset, severity and response to therapeutic agents, even among members of the same family who have the same mutation. A negative result in an individual with an aneurysm and/or connective tissue disease does not rule out a genetically inherited cause. Possible reasons for a negative result could be: the patient has a mutation in a gene not included in the testing panel the patient may have a mutation in a part of a gene that was not covered by the test the patient does not have a heritable form of an aneurysm Family members of a clinically affected individual with a negative test result may still be at risk for an aneurysm and/or connective tissue disease, and should be evaluated by a cardiologist and/or geneticist, if indicated. If an asymptomatic individual is negative for a mutation identified in a first-degree family member with an aneurysm, the result indicates that the individual is not at increased genetic risk for a familial aneurysm or connective tissue disease and instead has the same risk as a person in the general population. TAAD Clinician's Guide 4

6 A variant of unknown significance (VUS) is one of the most difficult results to interpret. This situation indicates that the pathogenic or benign role of the variant cannot be clearly established. In some cases, testing of other family members may help clarify the clinical significance of a VUS. If other relatives with an aneurysm and/or connective tissue disease are found to have the same variant, it is more likely that the variant is disease-causing. The greater the number of affected family members who carry the VUS, the greater is the likelihood that the VUS is pathogenic. Likewise, if an individual has apparently a sporadic aneurysm, the finding that a VUS is de novo (arose new in that individual and was not inherited from a parent) indicates that the variant is likely disease-causing. Management Management in TAAD and connective tissue diseases is impacted by family history as well as genetic test results. Management for affected and at-risk individuals may include: Lifestyle Modification Screening Medications Pregnancy Management Surgery Further Clinical Evaluation Avoidance of isometric exercise, weight lifting and competitive sports (specific recommendations exist for Marfan syndrome 2 as well as activities that could lead to a significant blow to the chest). At-risk individuals should also avoid tobacco use and maintain normal blood pressure. Aneurysms in other vessels and bicuspid aortic valve have been described in families with TAAD. Baseline imaging for at-risk family members of the ascending and descending thoracic aorta by echocardiogram, CT or MRA. Follow-up monitoring for at-risk relatives should be once every two years for aortic abnormalities if the initial assessment is normal. 3 Beta-blockers and other drugs that are helpful in slowing the rate of aortic enlargement in those with a diagnosis of Marfan syndrome may be recommended in other aneurysm-associated diagnoses. Individuals with aortic root dilatation or an aneurysm should be followed more closely during pregnancy to monitor for more rapid aortic enlargement. 3 Surgical repair is genotype- and family history-dependent. Surgical repair should be considered in familial TAAD cases when the diameter of the ascending aorta reaches approximately 4.2 to 5.0 cm (depending on the mutation or family history) or the rate of growth approaches 0.5 cm/year. 4 If other relatives have experienced dissection when the aorta is minimally enlarged, repair at an earlier enlargement stage should be considered. 3 Recommendations for surgical repair differ for Marfan syndrome, Loeys-Dietz syndrome and other related genetic syndromes. Evaluation by a clinical geneticist or healthcare provider familiar with connective tissue disease is recommended. 5

7 Resources for Patients Patient Support Organizations The John Ritter Foundation for Aortic Health (JRF): johnritterfoundation.org The Loeys Dietz Foundation: The National Marfan Foundation (NMF): Registry National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC): gentac.rti.org Genetic Counseling National Society of Genetic Counselors: References 1. GeneReviews: "Thoracic Aortic Aneurysms and Aortic Dissections" by Milewicz D et al. Genetests; Initial Posting: February 13, 2003; Last Revision: January 12, Maron et al. Circulation 2004;109: Hiratzka et al. Journal of the American College of Cardiology. 2010; 55: ACCF/AHA/ AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the Diagnosis and Management of Patients With Thoracic Aortic Disease: Executive Summary. JACC (14): Tran-Fadulu V et al. J Med Genet. 2009; 46: ; PMID Guo DC, Pannu H, Tran-Fadulu V, Papke CL, Yu RK, Avidan N, Bourgeois S, Estrera AL, Safi HJ, Sparks E, Amor D, Ades L, McConnell V, Willoughby CE, Abuelo D, Willing M, Lewis RA, Kim DH, Scherer S, Tung PP, Ahn C, Buja LM, Raman CS, Shete SS, Milewicz DM. Mutations in smooth muscle alpha-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet. 2007;39: Van Hemelrijk C et al. The Loeys-Dietz syndrome: An update for the clinician. Curr Opin Cardiol 25: , Malfait et al. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genet Med Oct;12(10): GeneReviews: Congenital Contractural Arachnodactyly Synonyms: Beals Syndrome, Beals-Hecht Syndrome Godfrey, M. Genetests: Initial Posting: January 23, 2001; Last Update: February 23, GeneReviews: MED12-Related Disorders by Lyons, M. Genetests: Initial Posting: June 23, 2008; Last Update: June 6, GeneReviews: Shprintzen-Goldberg Syndrome by Grealy, M. Genetests: Initial Posting: January 13, 2006; Last Update: June 13, Boileau C, et al. TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome. Nat Genet. 44:916 21, Lujan, J. E., Carlis, M. E., Lubs, H. A. A form of X-linked mental retardation with marfanoid habitus. Am. J. Med. Genet. 17: , Schwartz et al. The original Lujan syndrome family has a novel missense mutation (p.n1007s) in the MED12 gene. (Letter) J. Med. Genet. 44: , Robinson, P.et al. Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis. Am. J. Med. Genet. 135A: , TAAD Clinician's Guide 6

8 About GeneDx GeneDx is a highly respected genetic testing company, founded in 2000 by two scientists from the National Institutes of Health (NIH) to address the needs of patients and clinicians concerned with rare inherited disorders. Currently, GeneDx also offers whole exome sequencing, oligonucleotide microarray-based testing for detecting chromosomal abnormalities, testing for inherited eye disorders and autism spectrum disorders and gene panels for testing various forms of inherited cardiac disorders, mitochondrial disorders, neurological disorders and inherited cancer disorders. At GeneDx, our technical services are matched by our scientific expertise and customer support. Our growing staff includes more than 40 geneticists and genetic counselors specialized in clinical genetics, molecular genetics, metabolic genetics and cytogenetics who are just a phone call or away. We invite you to visit our website to learn more about us and the services we offer. 207 Perry Parkway Gaithersburg, MD T F E genedx@genedx.com GeneDx. All rights reserved /2014